Chagas' disease, caused by the protozoan parasite Trypanosoma cruzi, is a major health problem in many countries in Central and South America. An acute phase of the disease may occur several weeks after infection and a debilitating, often fatal chronic form of the disease may develop years later. The basis for the variation of the severity of the acute phase in humans is not understood nor is it clear what the relationship is of events occurring in the acute phase with the ultimate development of chronic disease. The long-term objective of the proposed work is to understand, using a murine model, how the early control of parasite proliferation may be related to the genetic basis of host resistance and to the development of chronic disease. Previous studies have indicated that a nonantibody-mediated control of parasite proliferation occurs in normal strains of mice during the first two weeks postinfection but is lacking in nu/nu mice and in the BXH-2 recombinant inbred strain. Parasite proliferation during the first intrecellular cycle of replication is increased by irradiation of the host and is greatest in those strains of mice showing the highest susceptibility to T. cruzi. The proposed work will determine what the control mechanism is in normal mice that limits parasite proliferation during the early acute phase, how this mechanism is impaired in BXH-2 mice and in irradiated mice, and if differences in the effectiveness of control of parasite proliferation in different strains determine their resistance or susceptibility to T. cruzi. Mechanisms of interest that will be examined in normal, BXH-2, and irradiated mice include NK cell activity, T cell-mediated killing, macrophage activation, and interferon and interleukin 2 production. The lack of control of early parasite proliferation in the BXH-2 strain is of particular interest since it has no known immunological deficit and makes a normal antibody response to T. cruzi. Genetic studies will determine if a single gene is responsible for the defect in these mice or if it is due to a particular combination of genes from the parental strains.